2002 Deep Brain Stimulation Consortium Meeting

Co-Sponsored by the NIH/National Institute of Neurological Disorders and Stroke and NIH/National Institute on Aging

The NIH Deep Brain Stimulation Consortium is a core group of researchers funded under an NINDS/NIA-sponsored RFA to explore
DBS and its therapeutic applications from several different disciplinary perspectives. The RFA specified that an annual workshop/meeting
among grantees and other interested members of the DBS community should be organized to develop collaborations among members
of the consortium and an enhanced sense of community among DBS researchers and practitioners.

The first of these annual meetings took place on in Rockville, MD on June 3-4, 2002, bringing together an international gathering
of physicians, basic scientists, patient advocates, industry representatives, and governmental officials to discuss issues
surrounding the use, technology, mechanisms, and ethics of deep brain stimulation (DBS).

In her welcoming remarks, National Institute of Neurological Disorders and Stroke (NINDS) Acting Director Audrey S. Penn,
M.D, pointed out that, although DBS is an important tool for the management of Parkinson's disease and certain other disorders
as we hunt for cures, the technology is not without adverse effects. "Your challenge," she told participants, "is to find
solutions to those problems."

William Heetderks, M.D., Ph.D., program director for the NINDS Repair and Plasticity cluster, described the major goals of
the meeting:

Reduce the incidence of severe complications associated with DBS

Develop DBS treatment strategies for Parkinson's and other disorders

Explore opportunities to expand the list of conditions for which DBS is indicated

"We also want to encourage collaborative efforts with tightly focused goals," stated Dr. Heetderks. "To that end, we have
developed a program to facilitate and fund training for junior scientists in institutions other than their own."

Representatives from nine of the eleven DBS Consortium member institutions currently funded by the NIH (NIA and NINDS) presented
brief snapshots of their work covering a wide range of topics, including: new device and guidance technologies, mechanisms
underlying the effects of DBS in different brain areas, DBS effects on non-motor symptoms of Parkinson's, beneficial and adverse
effects associated with DBS, and ethical concerns about the protection of patients undergoing surgical interventions and implantation
of devices that alter the brain.

The focus of the meeting then proceeded to engineering issues. Cha-Min Tang, M.D., Ph.D., of the University of Maryland School
of Medicine, and Joseph Schmitt, Ph.D., of LightLab Imaging LLC, described an optical system they are developing to help guide
and optimize the safe and effective placement of electrodes by mapping the brain's tomography and detecting the location of
blood vessels. (Damage to blood vessels is the most serious complication of DBS.) The system, known as optical coherence tomography
(OCT), could ultimately be used as an adjunct to the microelectrode recordings currently in use for verifying the appropriate
target in the brain. Other possible future OCT applications include delivery of stem cells or gene therapies into the brain
or spinal cord for diseases such as Parkinson's and amyotrophic lateral sclerosis, guidance during biopsies for brain tumors,
and placement of electrodes in epilepsy surgery.

Case Western Reserve University's Warren Grill, Ph.D., spoke about the need to expand the range between beneficial clinical
effects of DBS and its adverse side effects. One way to do this is to develop devices that use less power, which, in addition
to reducing tissue damage, would lengthen battery life. Dr. Grill pointed out that there are now over 29,000 possible setting
combinations for DBS devices and cautioned that we need post-implant correlation studies of implant location, motor effects,
and side effects to determine exactly what it is that is being stimulated or blocked and what the local versus circuit effects
of DBS are.

Turning to physiology, Peter L. Strick, Ph.D., from the University of Pittsburgh Medical Center and Pittsburgh Veterans Affairs
Medical Center, spoke about interactions of the parts of the brain known as the basal ganglia and cerebral cortex. Depending
on the position of DBS electrodes, a variety of different brain circuits may be stimulated that in turn may have effects on
the visual system, speech, emotional balance and psychiatric state. It is therefore imperative that we learn more about the
interrelationships of the various systems in order to determine the best placement for electrodes.

After briefly relating what is known about how DBS works, Marjorie E. Anderson, Ph.D., from the University of Washington,
focused on what remains controversial. Two questions that need answering are 1) Does DBS in the internal globus pallidus (GPi)
and subthalamic nucleus (STN), the parts of the brain most commonly targeted for Parkinson's disease, reduce the inhibitory
effects of the basal ganglia seen in Parkinson's disease? 2) Does DBS in GPi or STN increase the discharge rate of thalamic
neurons? Answering these questions may help resolve questions about why some people with essential tremor respond well to
DBS while others develop tolerance to stimulation and yet another group reaches a point where they no longer need stimulation.

Carol Walton, from the Parkinson Alliance, described that organization's efforts in support of the Michael J. Fox Foundation's
stem cell research initiative and the fund-matching program of the Tuchman Foundation. The Alliance also partners with New
York University's Re-Wired for Life Foundation, which sponsors a survey to record the total experiences of people before,
during, and after DBS surgery. This patient registry hopes to help answer questions about the long-term use of DBS.

The University of Toronto's Anthony E. Long, M.D., pointed out that Parkinson's is not really a single disease; it has a variety
of possible genetic and non-genetic origins, but response to levodopa is common to all forms. Additionally, since multiple
brain systems are involved, performing DBS in one area of the brain may not alleviate symptoms that originate in other areas.
Dr. Lang also noted that people who have undergone DBS appear to exhibit more dementia and psychiatric symptoms than people
who have not. The most significant predictor of benefit from DBS is a positive response to levodopa. DBS may ultimately fall
into several treatment categories: symptomatic, neuroprotective, and neuroregenerative. In order to determine which, we need
better outcome measures. Rating scales must be validated for symptoms such as postural instability and gait abnormalities.
We need standardized criteria for "optimization" of therapy and a way to improve masking of placebo effects.

Andres M. Lozano, M.D., Ph.D., also from the University of Toronto, described the motor and non-motor effects of DBS related
to the site of implantation. For Parkinson's disease, essential tremor, and dystonia, there are three surgical target locations
(the thalamus, the GPi, and the STN) and three surgical treatments (lesions, DBS, and tissue transplantation.) Symptoms improved
by DBS, in descending order of benefit, include levodopa-induced dyskinesias, tremor, rigidity, akinesia, and, to a lesser
extent, gait and postural disturbances. DBS works better for motor symptoms than it does for non-motor symptoms, which DBS
can actually cause or worsen. Symptoms that often do not respond well to drugs or surgery include problems with balance, speech,
cognition, depression, sleep, psychiatric, bladder, constipation, and impotence. Dr. Lozano also spoke of the cognitive side
effects of DBS, including mood changes, mania, emotional lability, aggression, psychosis, depression, and suicide, he has
seen in people whose electrodes were implanted in the STN. He suggested that, especially in older patients, the GPi may be
the better target, and suggested the need for comparative studies of DBS in GPi versus STN. Different symptoms demand different
surgical targets; the more we can refine targeting, the greater the clinical benefit and the less we will see unwanted side
effects.

The next speaker, Keith Wheatley, D. Phil., from the University of Birmingham in England, described a 10-year clinical trial
of surgery for Parkinson's disease just starting up. The trial will compare stimulation versus lesions in the thalamus, GPi,
and STN. Total recruitment will be between 400 and 600 patients in at least ten Centers in the United Kingdom and possibly
other countries. This will be the largest number of patients studied to date, and the length of the trial is expected to yield
much-needed data on possible long-term effects.

Frances M. Weaver, Ph.D. from Northwestern University and the Hines Veterans Affairs Hospital in Illinois, talked about a
newly formed partnership between the Department of Veteran's Affairs and NINDS to support a 5-year clinical trial comparing
DBS in the STN and GPi to best medical therapy. The 12-Center study will enroll approximately 316 patients.

Paul Sheehy, Ph.D., program director for the NINDS Neurodegeneration cluster, announced that a new round of grant awards would
soon be made that would add another eight institutions to the NIH DBS consortium. He ended the meeting by reiterating our
common goals by saying: "We need to make DBS work better and determine for whom it works best."